The present invention relates to compounds of the formula 
Q is selected from the group consisting of 
G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, hetrocyclo, 
L is O, S, SO, SO2 or NR13 or CR14R15;
W is O or NR16;
X is O, S, CHR17 or H, R18;
Z is O; S; H, R19 or R20, R21;
Y is selected from the group consisting of O; H, H; H, OR22; OR23, OR23; NOR24; H, NOR25; H, NR26R27; NHNR28R29; H, NHNR30R31; or CHR32; where OR23, OR23 can be a cyclic ketal;
B1 and B2 are selected from the group consisting of H, OR33, OCOR34, OCONR35R36, NR37R38 or NR39CONR40R41;
D is selected from the group consisting of NR42R43 or heterocyclo;
M is selected from the group consisting of S, Cxe2x95x90O, Sxe2x95x90O, SO2, NR44, or CR45R46;
J, E, U, and V are selected from carbon, oxygen, nitrogen or sulfur; or V may be absent;
R1, R2, R3, and R4, are selected from H, lower alkyl;
R5, R8, R9, R10 and R11 are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;
R6 and R7 are selected from the group consisting of H, alkyl, substituted alkyl, halogen, nitro, cyano, OR47, NR48R49, R50Cxe2x95x90O;
R17, R18, R22 and R23 are selected from the group consisting of H, alkyl, and substituted alkyl;
R20, R21, R24, R25, R26, R28, R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R47, R48, R50, R51, R52, R53, R54, R56, R57, R58, R59 and R61 are selected from the group of H, alkyl, substituted alkyl, aryl or substituted aryl;
R12, R13, R16, R27, R29, R31, R38, R43, R44, R49, R55 and R60 are selected from the group consisting of H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R51Cxe2x95x90O, R52OCxe2x95x90O, R53SO2, hydroxy, O-alkyl or O-substituted alkyl; when X is O then R16 is not R51Cxe2x95x90O, R52OCxe2x95x90O, and R53SO2; and wherein R44 is further amino and 
R14 and R15 are selected from the group consisting of H, halogen, alkyl, or substituted alkyl;
R19 is selected from the group consisting of H, alkyl, substituted alkyl, O-alkyl, O-substituted alkyl, NR54R55, R56Cxe2x95x90O; when L is O, S, or NR13 then R19 is not O-alkyl, O-substituted alkyl, NR54R55.
R45 and R46 are selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R56Cxe2x95x90O, R57OCxe2x95x90O, R58NHCxe2x95x90O, hydroxy, O-alkyl or O-substituted alkyl, NR59R60;
and any salts, solvates or hydrates thereof, with the proviso that
when Q is 
M is CR45R46 then W is only NR16.
Epothilones are macrolide compounds which find utility in the pharmaceutical field. For example, Epothilones A and B having the structures: 
have been found to exert microtubule-stabilizing effects similar to TAXOL and hence cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease, see Hofle et al., Angew. Chem. Int. Ed. Engl., 1996, Vol. 35, No. 13/14, pp. 1569.
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The expression xe2x80x9clower alkylxe2x80x9d refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, phenyl, substituted phenyl, heterocyclo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyoxy, heterocylooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH2), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to fluorine, chlorine, bromine and iodine.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
The term xe2x80x9caralkylxe2x80x9d refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to an aryl group substituted by, for example, one to four substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
The term xe2x80x9ccycloalkylxe2x80x9d refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclicxe2x80x9d and xe2x80x9cheterocycloxe2x80x9d refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl, and the like.
Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo [3,1-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and the like.
Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents. Also included are smaller heterocyclos, such as, epoxides and aziridines.
The term xe2x80x9cheteroatomsxe2x80x9d shall include oxygen, sulfur and nitrogen.
The compounds of formula I and II may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts can be obtained, for example, by exchanging the carboxylic acid protons, if they contain a carboxylic acid, in compounds of formula I and II with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by evaporation. Other salts can be formed as known to those skilled in the art.
The compounds for formula I and II form salts with a variety of organic and inorganic acids. Such salts include those formed with hydrogen chloride, hydrogen bromide, methanesulfonic acid, hydroxyethanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts are formed by reacting a compound of formula I and II in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by evaporation.
In addition, zwitterions (xe2x80x9cinner saltsxe2x80x9d) are formed.
Compounds of the formula I and II may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formula I and II) is a prodrug within the scope and spirit of the invention.
For example compounds of the formula I and II may form a carboxylate ester moiety. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid functionalities found on the disclosed ring structure(s).
Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, et al. (Acamedic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, xe2x80x9cDesign and Application of Prodrugs,xe2x80x9d by H. Bundgaard, p. 113-191 (1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and
e) N. Kakeya, et al., Chem Phar Bull, 32, 692 (1984).
It should further be understood that solvates (e.g., hydrates) of the compounds of formula I and II are also within the scope of the present invention. Methods of solvation are generally known in the art.
The compounds of formula I and II are microtubule-stabilizing agents. They are thus useful in the treatment of a variety of cancers, including (but not limited to) the following:
carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin; including squamous cell carcinoma;
hematopoictic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burketts lymphoma;
hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia;
other tumor, including melanoma, seminoma, tetratocarcinoma;
tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas;
tumors of mesenchymal origin, including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; and
other tumors including xenoderma pigmcntosum, keratoactanthoma, thyroid follivular cancer.
Compounds of formula I and II may also inhibit tumor angiogenesis, thereby affecting the growth of tumors. Such anti-angiogenesis properties of the compounds of formula I and II may also be useful in the treatment of certain forms of blindness related to retinal vascularization, arthritis, especially inflammatory arthritis, multiple sclerosis, restinosis and psoriasis.
Compounds of formula I and II may induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases. Compounds of formula I and II, as modulators of apoptosis, will be useful in the treatment of a variety of human diseases with aberrations in apoptosis including cancer (particularly, but not limited to follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostrate and ovary, and precancerous lesions such as familial adenomatous polyposis), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases (including but not limited to systemic lupus erythematosus, immune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer""s disease, AIDS-related dementia, Parkinson""s disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), AIDS, myelodysplastic syndromes, aplastic anemia, ischemic injury associated myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol induced liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases, and cancer pain.
The compounds of this invention are also useful in combination with known anti-cancer and cytotoxic agents and treatments, including radiation. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. Compounds of formula I and II can be used sequentially with known anticancer or cytotoxic agents and treatment, including radiation when a combination formulation is inappropriate. Especially useful are cytotoxic drug combinations wherein the second drug chosen acts in a different phase of the cell cycle, e.g. S phase, than the present compounds of formula I and II which exert their effects at the G2-M phase.
The present compounds may exist as multiple optical, geometric, and stereoisomers. Included within the present invention are all such isomers and mixtures thereof in the racemic form.
The compounds of this invention can be formulated with a pharmaceutical vehicle or diluent for oral, intravenous or subcutaneous administration. The pharmaceutical composition can be formulated in a classical manner using solid or liquid vehicles, diluents and additives appropriate to the desired mode of administration. Orally, the compounds can be administered in the form of tablets, capsules, granules, powders and the like. The compounds are administered in a dosage range of about 0.05 to 200 mg/kg/day, preferably less than 100 mg/kg/day, in a single dose or in 2 to 4 divided doses.
Compounds of formula I and II are prepared by the following schemes. 
Compounds of formula I where X is O, W is O, and Q is an aziridine group (I.e., M is NR44) can be prepared as outlined in Scheme 1. Compounds of formula 1A can be obtained from a fermentation process (see Angew. Chem. Int. Ed. Engl., 1996, 35, No. 13/14). A compound of formula 1B, where P1 is an oxygen protecting group such as triethylsilyl, can be prepared from a compound of formula 1A by known methods (See for example: Corey, E. J.; Venkateswarlu, A., J. Am. Chem. Soc., (1972) 94, 6190). Compounds of formula 1C and 1D are prepared by treatment with an azide, such as sodium azide, in polar solvents such as DMF. A compound of formula 1E can be prepared from compounds of formulas 1C and 1D by the Staudinger reaction (See for example: Ittah, Y., et al., J. Org. Chem., (1978) 43, 4271). A compound of formula 1F where R44 is not H can be prepared from a compound of formula 1E using methods known in the art. Deprotection of a compound of formula 1F using, for example when P1 is a triethylsilyl group, hydrogen fluoride in acetonitrile or tetra-n-butylammonium fluoride in THF provides a compound of formula I (1G) where X is O, W is O, Q is an aziridine group (M is NR44), and R1, R2, R3, R4 and R5 are defined as described above. 
Alternatively, a compound of formula 1E can be prepared as shown in Scheme 2. A compound of formula 2A, where P1 is an oxygen protecting group such as triethylsilyl, can be prepared from a compound of formula 1B by reaction of tungsten (VI) chloride and n-butyllithium (See for example: Sharpless, K. B., et al., J. Am. Chem. Soc., (1972) 94, 6538) in THF. A compound of formula 2B can be prepared from a compound of formula 2A by addition of a N-toluenesulfonamido group according to the method of Evans (i.e., Evans, D. A., et al., J. Org. Chem., (1991) 56, 6744). Deprotection of a compound of formula 2B using samarium iodide in THF/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone provides a compound of formula 1E (See for example: Vedejs, E., et al., J. Org. Chem., (1994) 59, 1602). Furthermore, a compound of formula 1B can be prepared from a compound of formula 2A by oxidation (See for example: Balog, A., et al., Angew. Chem. Int. Ed. Engl., (1996) 35, 2801). 
Compounds of formula I where X is O, W is O, and Q is a thiirane (i.e., M is S) can be prepared as outlined in Scheme 3. A compound of formula 4A can be prepared from a compound of formula 1B using potassium thiocyanate in alcoholic solution (See for example: Culvenor, C. C. J., et al., J. Chem. Soc., (1946) 1050). Deprotection of a compound of formula 4A using, for example when P1 is a triethylsilyl group, hydrogen fluoride in acetonitrile or tetra-n-butylammonium fluoride in THF provides a compound of formula I (4B) where X is O, W is O, Q is a thiirane group (i.e., M is S), and R1, R2, R3, R4 and R5 are defined as described above. Mild oxidation of a compound of formula 4A using stoichiometric or excess 3-chloroperoxybenzoic acid provides compounds of formula I where M is a Sxe2x95x90O or SO2 group, respectively. 
Compounds of formula I where X is O, W is O, and Q is an oxetane can be prepared as outlined in Scheme 4. A compound of formula 5A can be prepared from a compound of formula 1B, where R5 is a methyl group, by using lithium 2,2,6,6-tetramethylpiperidide and diethylaluminum chloride in benzene (See for example: Paquette, L. A., et al., J. Org. Chem., (1990) 55, 1589). A compound of formula 5B can be prepared from a compound of formula 5A by hydroboration and oxidation (See for example: Uzarewicz, A., et al., Rocz. Chem., (1977) 51, 723). A compound of formula 5C can be prepared from a compound of formula 5B by treatment with p-toluenesulfonylchloride (TsCl) in pyridine. A compound of formula 5D can be prepared from a compound of formula 5C by an intramolecular Williamson reaction according to the method of Moulines (i.e., Moulines, B. J., Leclercq, D., Picard, P., Synthesis, (1981) 550). Deprotection of a compound of formula 5D using, for example when P1 is a triethylsilyl group, hydrogen fluoride in acetonitrile or tetra-n-butylammonium fluoride in THF provides a compound of formula I (5E) where X is O, W is O, Q is an oxetane group, and R1, R2, R3, R4 and R5 are defined as described above. 
Alternatively, compounds of formula I where Q is an oxetane can be prepared as outlined in Scheme 5. Compounds of formula 6B and 6C can be prepared from a compound of formula 2A by Paterno-Buchi reaction of a carbonyl compound of formula 6A (See for example: Arnold, D. R., et al., Org. Photochem. Synth. (1971) 1, 51). Deprotection of compounds of formula 6B and 6C using, for example when P1 is a triethylsilyl group, hydrogen fluoride in acetonitrile or tetra-n-butylammonium fluoride in THF provides a compound of formula I (6D and 6E) where X is O, W is O, Q is an oxetane group, and R1, R2, R3, R4 and R5 are defined as described above. 
Compounds of formula I where X is O, W is O, and Q is a cyclobutane (i.e., L is CR14R5) can be prepared as outlined in Scheme 6. Compounds of formula 7B and 7C can be prepared from a compound of formula 2A by [2+2] cycloaddition of a substituted ketene compound of formula 7A (See for example: Krapcho, A. P., J. Org. Chem., (1966) 31, 2030). Deprotection of compounds of formula 7B and 7C using, for example when P1 is a triethylsilyl group, hydrogen fluoride in acetonitrile or tetra-n-butylammonium fluoride in THF provides a compound of formula I (7D and 7E) where X is O, W is O, Q is an cyclobutane group, and R1, R2, R3, R4 and R5 are defined as described above. 
Compounds of formula I where X is O, W is O, and Q is a 5-membered ring heterocycle can be prepared as outlined in Scheme7. Compounds of formula 8A and 8B can be prepared from a compound of formula 1B, where R5 is a hydrogen, by reaction of magnesium bromide diethyl etherate in dichloromethane. Compounds of formula 8C and 8D can be prepared from compounds of formula 8A and 8B by pyridinium chlorochromate oxidation in dichloromethane (See for example: White, J. D., et al., J. Org. Chem., (1995) 12, 3600). Compounds of formula 8F and 8G can be prepared from compounds of formula 8C and 8D by addition of a substituted thioamide of formula 8E (See for example: Cauvin, P. Compt. Rend., (1973) 276C, 1453). Deprotection of compounds of formula 8F and 8G using, for example when P1 is a triethylsilyl group, hydrogen fluoride in acetonitrile or tetra-n-butylammonium fluoride in THF provides a compound of formula I (8H and 8I) where X is O, W is O, Q is a 5-membered heterocycle, and R1, R2, R3, R4 and R5 are defined as described above. 
Compounds of formula I where X is O, W is O, and Q is a 6-membered ring heterocycle can be prepared as outlined in Scheme 8. Compounds of formula 9B and 9C can be prepared from compounds of formula 8C and 8D by reaction of diethyl zinc in THF with a Michael acceptor of formula 9A according to the method of Hansen (i.e., Hansen, M. M., et al., Organometallics, (1987) 6, 2069). Compounds of formula 9D and 9E can be prepared from compounds of formula 9B and 9C by addition of hydroxyl amine in ethanol (See for example: Chemistry of Heterocyclic Compounds, Wiley: N.Y., 1974; Vol. 14, Parts 1-5). Deprotection of compounds of formula 9D and 9E using, for example when P1 is a triethylsilyl group, hydrogen fluoride in acetonitrile or tetra-n-butylammonium fluoride in THF provides a compound of formula I (9F and 9G) where X is O, W is O, Q is a 6-membered heterocycle, and R1, R2, R3, R4 and R5 are defined as described above. 
A compound of formula 10G that is used for the preparation of compounds of formula I where X is O, W is O, and G is as defined above can be prepared as outlined in Scheme 9. Deprotection of a compound of formula 2A using, for example when P1 is a triethylsilyl group, hydrogen fluoride in acetonitrile or tetra-n-butylammonium fluoride in THF provides a compound of formula 10A. A compound of formula 10B can be prepared from a compound of formula 10A by pig-liver esterase mediated hydrolysis (See for example: Ohno, M., et al., Tetrahedron, (1984) 40, 145). A compound of formula 10C can be prepared from a compound of formula 10B by reaction of (trimethylsilyl)diazomethane in methanol and toluene (See for example: Hashimoto, N., et al., Chem. Pharm. Bull., (1981) 1397). A compound of formula 10D can be prepared from a compound of formula 10C by addition of t-butyldimethylsilyltriflate and 2,6-lutidine in dichloromethane (See for example: Askin, D., et al., J. Org. Chem., (1987) 52, 622). A compound of formula 10E can be prepared from a compound of formula 10D by reaction of AD-mix-xcex1 according to the method of Sharpless (i.e., Sharpless, K. B., et al., J. Org. Chem., (1992) 57, 2768). Compounds of formula 10F and 10G can be prepared from a compound of formula 10E by oxidative cleavage using lead tetraacetate in ethyl acetate (See for example: C. A. Bunton in K. B. Wiberg, ed., Oxidation in Organic Chemistry, Part A, Academic Press, New York, 1965, p. 367). Alternatively, a compound of formula 10G can be prepared from a compound of formula 10D by ozonolysis. 
Compounds of formula I where X is O, W is O, and G is a 1,2-disubstituted olefin can be prepared as outlined in Scheme 10. A compound of formula 11C can be prepared from compound of formula 11A and 11B using standard Wittig olefination known in the art (See for example: Meng, D., et al., J. Org. Chem., (1996) 61, 7999). A compound of formula 11D can be prepared from a compound of formula 11C by addition of an allyl metal reagent such as allylmagnesium bromide (Hoffmann, R. W. Angew. Chem. Int. Ed., Engl., (1982) 21, 555). A compound of formula 11E, where P2 is a triethylsilyl group, can be prepared from a compound of formula 11D by reaction of triethylsilyl chloride in DMF according to the method of Corey (See for example: Corey, E. J.; Venkateswarlu, A., J. Am. Chem. Soc., (1972) 94, 6190). A compound of formula 11F can be prepared from a compound of formula 11E by reaction of AD-mix-xcex1 according to the method of Sharpless (i.e., Sharpless, K. B., et al., J. Org. Chem., (1992) 57, 2768). A compound of formula 11G can be prepared from a compound of formula 11F by oxidative cleavage using lead tetraacetate in ethyl acetate (See for example: C. A. Bunton in K. B. Wiberg, ed., Oxidation in Organic Chemistry, Part A, Academic Press, New York, 1965, p. 367). A compound of formula 11H can be prepared from a compound of formula 11I by using a reducing agent such as sodium borohydride in methanol. A compound of formula 11I can be prepared from a compound with a formula 11H by reaction of iodine, imidazole and triphenylphosphine in toluene. A compound of formula 11J can be prepared from compound of formula 11I by reaction of triphenylphosphine in refluxing acetonitrile. A compound of formula 11K can be prepared from compounds of formula 11J and 10G using standard Wittig olefination (See for example: Bestmann, K. H., et al., Chem. Ber. (1979) 112, 1923). A compound of formula 11L can be prepared from a compound of formula 11K by selective deprotection using AcOH in THF. A compound of formula 11M can be prepared from a compound of formula 11L by reaction of LiOH in t-butanol and water. A compound of formula 11P can be prepared from a compound of formula 11M using typical macrolactonization coupling reagents such as 2,4,6-trichlorobenzoyl chloride, triethylamine, and 4-dimethylaminopyridine (See for example: Inanaga, J., et al., Bull. Chem. Soc. Jpn., (1979) 52, 1989). A compound of formula 11Q can be prepared from a compound of formula 11P by reaction of 1,1,1-trifluoroacetone according to the method of Yang (Yang, D., et al., J. Org. Chem., (1995) 60, 3887). A compound of formula I (11R) where X is O, W is O, G is a 1,2-disubstituted olefin, and R1, R2, R3, R4 and R5 are defined as described above can be prepared from compounds of formula 11P and 11Q as described in Schemes 1-9. 
Compounds of formula I where X is O, W is O, and G is a N, N-substituted amine as defined above can be prepared as outlined in Scheme 11. A compound of formula 12A can be prepared from a compound of formula 11R by addition of oxygen protecting groups (P1), such as a t-butyldimethlysilyl, with methods known in the art, followed by ozonolysis in dichloromethane. Reductive amination of compound of formula 12A with a compound of formula 12B using standard reagents such as sodium triacetoxyborohydride in acetic acid/dichloromethane provides a compound of formula 12C. Deprotection of a compound of formula 12C using, for example when P1 is a t-butyldimethylsilyl group, hydrogen fluoride in acetonitrile or tetra-n-butylammonium fluoride in THF provides a compound of formula I (12D) where X is O, W is O, G is N, N-disubstituted amine (i.e., D is NR42R43), and R1, R2, R3, R4 and R5 are defined as described above. 
Compounds of formula I where X is O, W is O, and G is a N, N-substituted amide as defined above can be prepared as outlined in Scheme 12. A compound of formula 13A can be prepared from a compound of formula I where G is 1-methyl-2-(2-methyl-4-thiazolyl)ethenyl by protection with triethylsilyl chloride (P1 is triethylsilyl) in DMF using methods known in the art followed by ozonolysis in dichloromethane. A compound of formula 13B can be prepared from a compound of formula 13C by reaction of sodium bis(trimethlysilyl)amide in THF followed by addition of chlorotrimethylsilane to quench the intermediate lithium enolate (See for example: House, H. O., et al., J. Org. Chem., (1971) 36, 2361). A compound of formula 13C can be prepared from a compound of formula 13B by ozonolysis. A compound of formula 13E can be prepared from compounds of formula 13C and 13D by standard amide bond coupling agents (i.e., DCC, BOP, EDC/HOBT, PyBrOP). Deprotection of a compound of formula 13E using, for example when P1 is a triethylsilyl group, hydrogen fluoride in acetonitrile or tetra-n-butylammonium fluoride in THF provides a compound of formula I (13F) where X is O, W is O, G is N, N-disubstituted amide, and R1, R2, R3, R4 and R5 are defined as described above. 
As shown in Scheme 13, compounds of formula I where W is NR16 can be prepared from compounds of formula I where W is O. A compound of formula 14A can be prepared from a compound of formula 11R by reaction of sodium azide and tetrakis(triphenylphosphine)palladium in THF/water. Reduction of a compound of formula 14A using Adam""s catalyst (PtO2) or a trialkylphosphine in ethanol provides a compound of formula 14B. Intramolecular cyclization of compound of formula 14B using diphenylphosphoryl azide and sodium bicarbonate or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiilmide in DMF provides a compound of formula I (14C), where W is NR16 (R16 is H). 
Compounds of formula II can be prepared from a compound of formula I, where B1 and B2 are hydroxyl groups, as shown in Scheme 14. A compound of formula 15A can be prepared from compounds of formula I by addition of formyl groups using standard conditions such as formic acid, triethylamine, acetic anhydride in dichloromethane. Elimination of a compound of formula 15A using 1,8-diazabicyclo[5.4.0]undec-7-ene in dichloromethane provides a compound of formula 15B. Deprotection of a compound of formula 15B using ammonia in methanol provides a compound of formula II (15C). 
As shown in Scheme 15, compounds of formula I where X is S or dihydrogen can be prepared from compounds of formula I where X is O. A compound of formula 16A, where X is S, can be prepared from a compound of formula I where X is O by reaction of triethylsilyl chloride(P1) with methods known in the art, followed by the reaction of Lawesson""s reagent in toluene (See for example: Nicolaou, K. C., et al., J. Amer. Chem. Soc., (1990) 112, 6263). Reduction of a compound of formula I (16A) using triphenyltin hydride and 2,2xe2x80x2-azobisisobutyronitrile in benzene, followed by deprotection using standard methods such as acetic acid in THF (See for example: Nicolaou, K. C., et al., Chem. Comm., (1995) 1583) provides a compound of formula I (16B), where X is dihydrogen. 
Alternatively, as shown in Scheme 16, compounds of formula I where X is H, R18 can be prepared from compounds of formula I where X is O. A compound of formula 17A can be prepared from a compound of formula I by reaction of triethylsilyl chloride in DMF using standard methods known in the art. A compound of formula 17B can be prepared from a compound of formula 17A by reaction of diisobutylaluminum hydride followed by acetic anhydride according to the method of Dahanukar (i.e., Dahanukar, V. H., et al., J. Org. Chem. (1996) 61, 8317). Reaction of a compound of formula 17B with dialkylzinc, (R18)2Zn, in dichloromethane according to the method of Rychnovsky (Rychnovsky, S. D., et. al., J. Org. Chem. (1997) 62, 6460) provides a compound of formula 17C. Deprotection of a compound of formula 17C using, for example when P1 is a triethylsilyl group, hydrogen fluoride in acetonitrile or tetra-n-butylammonium fluoride in THF provides a compound of formula I (17D) where X is H, R18 and R1, R2, R3, R4 and R5 are defined as described above. 
The hydroxyl groups of a compound of formula I, such as 1A (where R1-4 are methyl and R6 is 2-methyl-4-thiazolyl), can be optionally protected as, for example, triethylsilyl ethers using methods known in the art. A compound of formula 18B where X is halogen, can be prepared from a compound for formula 18A by treatment with certain metal halide salts such as magnesium bromide. A compound of formula 18C can be prepared from a compound of formula 18B by treatment with a metal azide salt such as lithium azide. A compound of formula 18D can be prepared from a compound of formula 18C by Mitsunobu reaction using, for example, triphenylphosphine and a carboxylic acid such as 4-nitrobenzoic acid. A compound of formula 18E can be prepared from a compound of formula 18D by hydrolysis or ammoniolysis of the ester group using, for example, a solution of ammonia in methanol. Optionally, a compound of formula 18E where P1 is an oxygen protecting group such as triethylsilyl can be deprotected using trifluoroacetic acid in dichloromethane, or other methods known in the art. Reduction of the azido group and subsequent cyclization of a compound of formula 18E with a reducing agent such as a triaryl- or trialkylphosphine provides a compound of formula I, such as 18F (where R1-4 are methyl and R6 is 2-methyl-4-thiazolyl). 
Alternatively, a compound of formula 18E where P1 is an oxygen protecting group, can be converted to a alkyl or aryl sulfonyl chloride. Reduction of the azido group and subsequent cyclization of a compound of formula 19A using a reducing agent such as a triaryl- or trialkylphosphine or with hydrogen and Lindlar""s catalyst (Pd, CaCo3/Pb) provides a compound of formula I such as 18F (where R1-4 are methyl and R6 is 2-methyl-4-thiazolyl). 
Alternatively, a compound of formula 18C where P1 is an oxygen protecting group, can be converted to a compound of formula 20A where X is a halogen by treatment with, for example, triphenylphosphine and a carbon tetrahalide. Reduction of the azido group and subsequent cyclization of a compound of formula 20A using a reducing agent such as a triaryl- or trialkylphosphine or with hydrogen and Lindlar""s catalyst (Pd, CaCO3/Pb) provides a compound of formula I, such as 18F (where R1-4 are methyl and R6 is 2-methyl-4-thiazolyl).
The in vitro assessment of biological activity of the compounds of Formula I and II was performed as follows:
Twice cycled (2xc3x97) calf brain tubulin was prepared following the procedure of Williams and Lee (see Williams, R.C., Jr., and Lee, J. C. Preparation of tubulin from brain. Methods in Enzymology 85, Pt. D: 376-385, 1982) and stored in liquid nitrogen before use. Quantification of tubulin polymerization potency is accomplished following a modified procedure of Swindell, et al., (see Swindell, C. S., Krauss, N. E., Horwitz, S. B., and Ringel, I. Biologically active taxol analogues with deleted A-ring side chain substituents and variable C-2xe2x80x2 configurations. J. Med. Chem. 34: 1176-1184, 1991). These modifications, in part, result in the expression of tubulin polymerization potency as an effective concentration for any given compound. For this method, different concentrations of compound in polymerization buffer (0.1M MES, 1 mM EGTA, 0.5 mM MgCl2, pH 6.6) are added to tubulin in polymerization buffer at 37xc2x0 in microcuvette wells of a Beckman (Beckman Instruments) Model DU 7400 UV spectrophotometer. A final microtubule protein concentration of 1.0 mg/ml and compound concentration of generally 2.5, 5.0, and 10 xcexcM are used. Initial slopes of OD change measured every 10 seconds were calculated by the program accompanying the instrument after initial and final times of the linear region encompassing at least 3 time points were manually defined. Under these conditions linear variances were generally  less than 10xe2x88x926, slopes ranged from 0.03 to 0.002 absorbance unit/minute, and maximum absorbance was 0.15 absorbance units. Effective concentration (EC0.01) is defined as the interpolated concentration capable of inducing an initial slope of 0.01 OD/minute rate and is calculated using the formula: EC0.01=concentration/slope. EC0.01 values are expressed as the mean with standard deviation obtained from 3 different concentrations. EC0.01 values for the compounds in this invention fall in the range 0.01-1000 xcexcM.
Cytoxicity was assessed in HCT-116 human colon carcinoma cells by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphenyl)-2H-tetrazolium, inner salt) assay as reported in T. L. Riss, et. al., xe2x80x9cComparison of MTT, XTT, and a novel tetrazolium compound MTS for in vitro proliferation and chemosensitivity assays,xe2x80x9d Mol. Biol. Cell 3 (Suppl.):184a, 1992. Cells were plated at 4,000 cell/well in 96 well microtiter plates and 24 hours later drugs were added and serial diluted. The cells were incubated at 37xc2x0 form 72 hours at which time the tetrazolium dye, MTS at 333 xcexcg/ml (final concentration), in combination with the electron coupling agent phenazine methosulfate at 25 xcexcM (final concentration) was added. A dehydrogenase enzyme in live cells reduces the MTS to a form that absorbs light at 492 nM which can be quantitated spectrophotometrically. The greater the absorbance the greater the number of live cells. The results are expressed as an IC50, which is the drug concentration required to inhibit cell proliferation (i.e. absorbance at 450 nM) to 50% of that of untreated control cells. The IC50 values for compounds of this invention fall in the range 0.01-1000 nM. As preferred compounds there are formula I and II compounds wherein
Q is selected from the group consisting of 
Most preferred are compounds of formulas I and II Wherein 